PROJECT SUMMARY It is widely reported that neglected children become neglectful parents. This cycle of child maltreatment is responsible for a large proportion of child abuse and neglect in the United States. Presently there are no rodent models that directly investigate how dysregulation of the maternal brain mediates neglect or how the early experience of neglect is transmitted across generations. The overall objective of this proposal is to develop a clinically relevant mouse model to identify molecular mechanisms of infant neglect that can be targeted to reverse the cycle of pathological parenting. The medial preoptic area of the hypothalamus (MPOA) coordinates parental behavior by inhibiting neural pathways involved in infant avoidance and activating pathways involved in approach. Hormonal stimulation associated with late pregnancy and birth is one factor that determines which pathway infant stimuli will activate in mother rats. Mother-infant interaction at birth, in the context of hormonal exposure, induces plasticity in the approach pathway that supports the continuation of mothering behavior. Our central hypothesis is that plasticity in the maternal neural circuit is regulated by experience-driven chromatin modifications. Chromatin is the complex of DNA compactly coiled around histone proteins. The post- translational modifications of histones by histone acetyltransferase (HAT) enzymes leave ?epigenetic marks that exist above the level of the genome and control gene expression. Our preliminary data indicate that the HAT activities of the chromatin-modifying enzyme CREB binding protein (CBP) critically mediate plasticity in the maternal neural circuit. Aim 1 will determine the extent to which conditional mutation of CBP-HAT causes maternal neglect and whether wildtype female offspring that experience early life neglect become neglectful mothers in adulthood. Aim 2 will determine the extent to which the behavioral transmission of neglect from mother-to-daughter is linked to dysfunction in CBP-HAT in the maternal neural circuit in response to infant stimuli at birth and Aim 3 will identify the critical developmental time point when the maternal neural circuit is programmed for neglect/care. To determine the epigenetic program that mediates the behavioral transmission of neglect, we propose a highly innovative method in which neurons that are activated (fire action potentials) during particular experiences become ?Tagged? with a green fluorescent protein (GFP) that is used to isolate these cells for downstream molecular analyses. Aim 4 will use this technique to examine the downstream molecular pathways that mediate the transmission of neglect in select neurons that are activated during the early life experience of neglect or neurons that are activated during the adult onset of neglect. Importantly, the cycle of child maltreatment cannot be broken without an understanding of the neurobiological mechanisms that mediate and perpetuate neglect. The proposed work is expected to make a significant impact on the development of therapeutic interventions that break the cycle of child maltreatment and reverse maternal neglect.